Process for producing bone cement containing active substances

ABSTRACT

The invention relates to a process for the preparation of bone cements comprising active compound and to bone replacement materials or implantable drug depots produced therefrom. The bone cement is composed of a solid component and a liquid component. The liquid component is dissolved in an organic solvent whose proportion does not exceed 50% by weight based on the liquid component, and this solution is mixed with the solid component.

The invention relates to a process for the preparation of bone cementscomprising active compound and to bone replacement materials orimplantable drug depots which can be produced therefrom.

Bone cements, bone replacement materials and implantable drug depotsbased on acrylate polymers have been known for a long time. Polymermaterials based on acrylic and/or methacrylic esters have provedthemselves here on the basis of their biocompatibility, their excellentstrength properties, their favourable properties in respect of therelease of incorporated pharmaceutical active compounds and, last butnot least, on the basis of their utility-oriented processability.

Customary bone cements are composed of from about 50 to 75% by weight ofa solid component which consists of a finely divided polymer of acrylicand/or methacrylic esters and, if desired, of further additives such aspolymerization catalysts, X-ray contrast media, fillers and colorants,and of from about 25 to 50% by weight of a liquid component whichconsists of an acrylic and/or methacrylic ester monomer and, if desired,further additives such as polymerization accelerators and stabilizers.For use, the solid and the liquid component are combined to form aliquid to semisolid paste, which is optionally brought into a desiredshape or is applied at the implantation site of a prosthesis to cementit in. The composition cures by means of the polymerization reactionthat is induced with the mixing of the components.

A very common bone cement, for example, is one which, in a standardpack, comprises two bags of about 40 g of polymer powder each and twoampoules of 20 ml of monomer liquid each. The powder is a fine beadpolymer of methyl methacrylate with a copolymer content of methylacrylate. About 0.5% of dibenzoyl peroxide is added to the powder as acatalyst. During preparation the material is identified bycopolymerizing small amounts of chlorophyll. The powder additionallycomprises a customary X-ray contrast medium such as, for example,zirconium dioxide. The associated liquid consists of monomeric methylmethacrylate, to which about 0.7% of dimethyl-p-toluidine is added as apolymerization accelerator and small amounts of hydroquinone are addedas a stabilizer. This liquid is also, in general, coloured with a smallamount of chlorophyll for identification. The powder, packaged inpolyethylene bags, is sterilized with ethylene oxide. The liquid issubjected to sterile filtration and dispensed into glass ampoules.

When 2 parts by weight of powder are mixed together with one part byweight of liquid, the dibenzoyl peroxide reacts with thedimethyl-p-toluidine in the liquid, which prompts the free-radicalpolymerization. The mixture is formulated such that it can be used as adoughy paste after only about one minute. This paste remains kneadablefor a number of minutes and then begins to cure, giving off heat as itdoes so. After about 5 to 10 minutes the polymerization is essentiallyat an end. During the polymerization phase, for as long as the paste isstill deformable, it can be brought into any desired shape, i.e. it can,for example, be introduced directly into the body for filling bonecavities or for cementing prostheses or can be used to produce shapedarticles which cure outside the body and can then be used at any desiredpoints of the body.

For numerous indications it is desirable for the bone cement to comprisepharmaceutical active compounds. Thus, bone cements comprisingcytostatics can be employed for remedying bone defects following theremoval of bone tumours. Bone cements which comprise antibiotics,antiseptics and, if desired, substances which promote bone growth areadvantageous for cementing prostheses and for osteosynthesis. Shapedarticles of bone cements comprising active compound can be implantedinto soft tissue as local depots of active compound with delayed releaseof the active compound. Customary commercial bone cements with addedantibiotics (e.g. Septopal®) are occasionally also used asactive-compound vehicles for treating local infections. In addition,other antibiotics are added to such cements in order to increase theactivity.

EP 0 202 445 A1, for example, describes such a bone cement comprisingcytostatics, and also describes a drug depot produced therefrom whichhas particularly favourable release properties. This document revealsthat the respective active compound is mixed in with the base materialof the bone cement, i.e. with the prepolymer and/or with the monomer, asa finely divided powder, so that it is then present in homogeneousdistribution within the corresponding polymer.

EP 0 701 824 A2 describes a process for producing bone cementscomprising active compound, where the active compound is dissolved in anorganic solvent and this solution is mixed with the liquid component orwith the solid component. In this way, all three components of the bonecement can be provided in sterile form.

The addition of release promoters as powders to the cement is known perse. For example, DE 26 51 441 C2 describes the addition of amino acids.

The preformulated bone cement components, which are optimized primarilyin respect of their mechanical properties or in respect of simplicity ofsterilization of the components, however, do not meet the requirementsthat must be met by a medical product intended for implantation in thebody, since they have only suboptimal properties for use asactive-compound vehicles.

Manual mixing, such as the addition of release promoters as powders tothe cement (e.g. salt, sugars, amino acids) as well, has thedisadvantage that it is virtually impossible to achieve homogeneous andreproducible mixing. A nonhomogeneous mixture necessarily requires largeadditions of active compounds and auxiliaries in order to achieve thedesired release. When customary commercial bone cements comprisingactive compound are used, the release remains usually well below thetherapeutically desirable level. This is particularly true of implantshaving adverse geometric proportions (for example cement fillings).

The object was therefore to develop a process with which it is possibleto provide, simply, bone cements and/or their precursor and successorproducts, comprising active compound, where the kinetics of the releaseof active compound are at the fore, i.e. where improved release of theactive compound is achieved.

It has now been found that by mixing appropriate solvents in with themonomer component of bone cements the disadvantages described areavoided and it is possible to produce, from cements loaded with activecompound, highly effective, implantable active-compound vehicles. Asignificantly higher release of active compound is achieved, thepreparation of the bone cement is simple, and the amounts of activecompound required are small.

The invention therefore provides a process for the preparation of a bonecement, bone replacement material or corresponding, implantable drugdepot which comprises one or more active compounds and is based onacrylic and/or methacrylic ester polymers, by mixing a

solid component (i) consisting essentially of polymeric acrylic and/ormethacrylic ester in a proportion, relative to the bone cement, of from50 to 75% by weight, and of one or more pharmaceutical active compoundswith a

liquid component (ii) consisting essentially of monomeric acrylic and/ormethacrylic ester in a proportion of from 25 to 50% by weight, to form aliquid to semisolid, polymerizable paste, and, if desired, by shapingand curing thereof, characterized in that the liquid component (ii) isdissolved with an organic solvent whose proportion does not exceed 50%by weight based on (ii) and this solution is mixed with the solidcomponent (i).

With the process according to the invention it is possible to use allcustomary bone cements based on acrylate/methacrylate and/or thestarting materials customary for them. Bone cements of this kind areavailable commercially. Their composition and the manner of theirpreparation are familiar to the skilled worker.

To prepare a bone cement comprising active compound, it is envisagedaccording to the invention to dissolve the monomer component in anorganic solvent and then to mix this monomer solution with the finelydivided polymeric solid component of the bone cement, the lattercomponent comprising the active compound. In preparing the cementmixture the solvent plays no part in the reaction, or participates as apolymerization partner, as in the case of vinylpyrrolidone. The monomersolution is subjected to sterile filtration beforehand, while the solidcomponent is subjected to a final sterilization by means of radiationand/or ethylene oxide.

Solvents suitable for preparing the monomer solution are essentially allcustomary organic solvents. Examples of preferred solvents are2-pyrrolidone, N-methylpyrrolidone, dimethyl sulfoxide (DMSO),tetrahydrofuran (THF), dioxane, ethylene glycol, propanediol,vinylpyrrolidone or mixtures of these solvents. It is judicious toselect those solvents in which the intended monomer dissolves well. Theamount of solvent is chosen so as not to exceed 50% by weight, based onthe liquid monomer. This ensures that, when mixing the components toform the ready-to-use bone cement, the processing properties, curingcharacteristics and mechanical strength of the cured bone cement do notalter too greatly. The amount of solvent chosen is preferably such thatits proportion is from 1 to 25% by weight, in particular from 5 to 20%by weight, based on the liquid monomer component.

The amount of pharmaceutical active compound employed which is mixed inwith the bone cement is dependent on its specific activity, on themedical indication and on the particular set of requirements to whichthe bone cement or the bone replacement material or the drug depot to beprepared from it is subject. Generally speaking, a proportion ofpharmaceutical active compound of from 0.1 to 5% by weight, based on theoverall amount of bone cement, is sufficient; in some individual cases,especially when preparing implantable drug depots, however, theproportion of active compound may be even higher, for instance up to 40%by weight.

Suitable active compounds are preferably cytostatics such asmethotrexate, cisplatin, cyclophosphamide, fluorouracil, doxorubicin,etc., antibiotics such as vancomycin, netilmicin, gentamicin,clindamycin, vancomycin, teicoplanin, etc., and also antiseptics, andbone growth promoters.

It has surprisingly been found that the release properties of bonecement comprising, say, antibiotics, which has been prepared by theprocess according to the invention, are considerably better than if themonomer component is mixed directly in with the solid component, as hasbeen the case to date.

Of course, the release properties of the active compound can also beinfluenced and, if appropriate, improved further by means of the knownand customary additives. Suitable additives of this kind are aminoacids, such as arginine, and also hydroxyapatile or sodium bicarbonate,as far as possible in finely divided form with particle sizes below 100μm. By means of additives of this kind it is possible, in particular, toregulate the initial concentration of the release of active compound.

The solid component, which is usually in the form of a bead polymer ofmethyl methacrylate-methyl acrylate copolymer with particle sizes ofbetween 5 and 250 μm, comprises a polymerization catalyst, such asdibenzoyl peroxide, and the pharmaceutical active compound. It may alsocomprise X-ray contrast media, such as zirconium dioxide, for example,dyes for identification, such as chlorophyll, and also fillers and, ifdesired, further additives. Examples of common fillers areosteoinductive or osteoconductive calcium phosphates, such as, inparticular, hydroxyapatile and tricalcium phosphate. The proportion ofall these additives can vary widely and is dependent on the respectiveset of requirements to which the bone cement and/or the correspondingsuccessor products are subject. In general it barely exceeds 30% byweight, based on the solid component. The liquid monomer component,methyl methacrylate, generally comprises a polymerization accelerator,such as dimethyl-p-toluidine, and hydroquinone as stabilizer, in theamounts customary for these additives. It is also possible for dyes andany other judicious additives to be present. The solid component can besterilized readily with γ radiation or with ethylene oxide; the liquidcomponent can be subjected to sterile filtration. Both components can bedispensed separately and under sterile conditions into appropriatecontainers.

The bone cement containing active compound is judiciously provided inthe form of a kit composed of separate packs of the two principalcomponents. Component (a) comprises the solid component, consisting of afinely divided polymer of acrylic and/or methacrylic esters, apharmaceutical active compound and, if desired, further additives, suchas polymerization catalysts, X-ray contrast media, fillers and dyes,whose proportion is from about 50 to 75% by weight of the bone cement.Component (b) comprises the liquid component, consisting of an acrylicand/or methacrylic acid monomer and, if desired, further additives suchas polymerization accelerators, stabilizers and release promoters, whoseproportion is from about 25 to 50% by weight of the bone cement, in anorganic solvent whose proportion does not exceed 50% by weight based onthe liquid component.

The amounts of the components are preferably tailored to one another insuch a way that the entire contents of the two packs are combined withone another. The tailoring of amounts is performed in accordance withthe intended utility and depends on whether a cement of low, medium orhigh viscosity is required. The solid component in this case has beensubjected to a final sterilization by means of radiation or ethyleneoxide, the liquid monomer solution has been subjected to sterilefiltration, and both components are dispensed under sterile conditionsinto appropriate packaging.

It is judicious to supplement this kit with a device for mixing and/orapplying the bone cement. Appropriate devices are known and common.Preferably, appropriate devices enable the bone cement to be mixed undervacuum and make it possible for the cement to be applied in combinationusing a bone cement syringe.

The preparation of the ready-to-use bone cement comprising activecompound and its further processing are carried out in full analogy withprior art bone cement systems. The bone cement comprising activecompound can be used in a customary manner during the liquid or plasticstage for the implantation of bone prostheses. The surgeon is also ableto process the composition to give shaped articles of any shape andsize, and, after curing, to implant them as local depots of activecompound into the areas of the body that are to be treated. Implantabledrug depots of this kind can also be offered in prefabricated form.

EXAMPLE 1

A bone cement comprising 2 g of vancomycin as powder in 40 g ofOsteopal® cement powder (consisting of polymethyl methacrylate,chlorophyll, benzoyl peroxide and zirconium dioxide) is stirred with 20ml of methyl methacrylate monomer. 3 further samples are preparedcorrespondingly with methyl methacrylate monomer to which 0.2, 1.0 and 4ml, respectively, (1, 5 and 20% by weight, respectively,) of propanediolhave been added. The runny cement paste is introduced into a two-partmetal mould having spherical cavities with a diameter of 7 mm. After thecement has cured, the spheres are removed and the release of the activecompound is determined in vitro by a standardized method.

Table 1 shows the daily release of vancomycin in μg/ml from therespective bone cement spheres. This increases on addition of 1 ml (5%by weight) of propanediol to the monomer by a factor of 5 at its peak(day 1). Even at later points in time, the release remains from about 3to 5 times as great as with the initial cement.

                  TABLE 1                                                         ______________________________________                                        Release of vancomycin [μg/ml]                                                   0% by weight                                                                             1% by weight                                                                             5% by weight                                                                           20% by weight                             Day  propanediol                                                                              propanediol                                                                              propanediol                                                                            propanediol                               ______________________________________                                        0.1  25.88      34.69      74.70    70.20                                     1    47.06      74.17      233.61   238.63                                    2    25.75      35.45      86.03    129.44                                    3    18.49      24.84      59.11    100.47                                    4    14.49      26.30      51.24    86.21                                     5    14.87      29.68      47.00    79.06                                     6    17.33      28.25      57.27    80.59                                     7    11.78      21.53      48.86    56.06                                     8    9.78       20.50      37.78    47.01                                     9    10.41      17.30      23.89    41.64                                     10   8.86       12.97      23.76    33.54                                     14   5.19       9.71       15.13    23.89                                     28   2.26       3.36       5.46     21.42                                     84   0.79       1.09       2.78     4.31                                      ______________________________________                                    

EXAMPLE 2

A bone cement comprising 2 g of netilmicin as powder in 40 g of Osteopalcement powder is stirred together with 20 ml of methyl methacrylatemonomer. 3 further samples are prepared correspondingly with methylmethacrylate monomer to which 0.2, 1.0 and 4 ml, respectively, (1, 5 and20% by weight, respectively,) of propanediol have been added. The runnycement paste is introduced into a two-part metal mould having sphericalcavities with a diameter of 7 mm. After the cement has cured, thespheres are removed and the release of the active compound is determinedin vitro in accordance with a standardized method.

Table 2 shows the daily release of netilmicin in μg/ml from therespective bone cement spheres. The release of netilmicin is relativelyhigh at its peak even in the initial cement, but then falls off rapidly.The addition of 1 ml of propanediol (5% by weight) doubles the peakvalue (day 1). Over the subsequent days, up to day 9, the differencebecomes larger up to a factor of about 10 and then remains virtuallyconstant.

                  TABLE 2                                                         ______________________________________                                        Release of netilmicin [μg/ml]                                                   0% by weight                                                                             1% by weight                                                                             5% by weight                                                                           20% by weight                             Day  propanediol                                                                              propanediol                                                                              propanediol                                                                            propanediol                               ______________________________________                                        0.1  100.99     285.95     282.95   308.77                                    1    335.62     498.29     634.96   783.22                                    2    52.05      60.06      142.97   248.30                                    3    34.96      32.55      82.82    170.64                                    4    23.16      21.00      96.48    150.83                                    5    29.16      22.62      64.50    125.63                                    6    15.83      26.94      121.44   113.52                                    7    17.64      10.53      125.40   114.85                                    8    9.45       5.06       88.14    92.98                                     9    5.53       4.59       58.96    50.36                                     10   4.45       3.30       50.91    42.47                                     14   3.24       1.74       35.09    23.04                                     28   1.69       1.05       15.97    5.42                                      84   0.43       0.23       3.76     1.14                                      168  0.22       0.20       2.36     0.47                                      ______________________________________                                    

What is claimed is:
 1. Process for the preparation of a bone cement,bone replacement material or corresponding, implantable drug depot whichcomprises one or more active compounds and is based on acrylic and/ormethacrylic ester polymers, said process comprising mixing asolidcomponent (i) consisting essentially of polymeric acrylic and/ormethacrylic ester in a proportion, relative to the bone cement, of from50 to 75% by weight, and of one or more pharmaceutical active compoundswith a liquid component (ii) consisting essentially of monomeric acrylicand /or methacrylic ester in a proportion, relative to the bone cement,of from 25 to 50% by weight, to form a liquid to semisolid,polymerizable paste, and, optionally, the shaping and curing thereof,wherein the liquid component (ii) is dissolved with an organic solventwhose proportion is from 1 to 25% by weight based on (ii) and theresultant solution is mixed with the solid component (i), and whereinsaid solvent is 2-pyrrolidone, N-methylpyrrolidone, vinylpyrrolidone,dimethyl sulfoxide, tetrahydrofuran, dioxane, propanediol orcombinations thereof.
 2. Process according to claim 1, wherein theproportion of solvent is from 5 to 20% by weight, based on the liquidcomponent.
 3. Process according to claim 1, wherein the solid componentis subjected to a final sterilization by means of radiation, ethyleneoxide, or both, and the liquid component is subjected to sterilefiltration.
 4. Kit for the preparation of bone cement which promotes therelease of active compound, said kit comprising separate packs of(a) asolid component whose proportion is from about 50 to 75% by weight ofthe bone cement, consisting essentially of a finely divided polymer ofacrylic and/or methacrylic esters and of a pharmaceutical activecompound, and (b) a solution of a liquid component, whose proportion isfrom about 25 to 50% by weight of the bone cement, consistingessentially of an acrylic and/or methacrylic acid monomer in an organicsolvent whose proportion of solvent is from 1 to 25% by weight based onthe liquid component, and wherein said solvent is 2-pyrrolidone,N-methylpyrrolidone, vinylpyrrolidone, dimethyl sulfoxide,tetrahydrofuran, dioxane, propanediol or combinations thereof.
 5. Kitaccording to claim 4, further comprising a device for mixing the bonecement.
 6. Kit according to claim 4, wherein the pack unit (a) has beensubjected to a final sterilization by means of radiation, ethyleneoxide, or both, and the contents of the pack unit (b) have beensubjected to sterile filtration.
 7. Kit according to claim 4, furthercomprising a device for applying the bone cement.
 8. Kit according toclaim 5, further comprising a device for applying the bone cement. 9.The process according to claim 1, wherein the pharmaceutical activecompound is a cytostatic agent.
 10. The process according to claim 9,wherein the cytostatic agent is methotrexate, cisplatin,cyclophosphamide, fluoracil, or doxorubicin.
 11. The process accordingto claim 1, wherein the pharmaceutical agent is an antibiotic.
 12. Theprocess according to claim 11, wherein the antibiotic is vancomycin,netilmicin, gentamicin, clindamycin, vancomycin, or teicoplanin.
 13. Theprocess according to claim 1, wherein the polymer is polymethylmethacrylate.
 14. The process according to claim 1, wherein thepharmaceutical active agent is an antiseptic.
 15. The process accordingto claim 1, wherein the pharmaceutical active agent is a bone growthpromoter.
 16. The process according to claim 1, further comprising aminoacids, hydroxyapatile, sodium bicarbonate, x-ray contrast media, or dye.17. The process according to claim 15, wherein the x-ray contrast mediais zirconium dioxide.
 18. The process according to claim 1, wherein theproportion of pharmaceutical active compound is from 0.1 to 5% byweight, based on the bone cement.
 19. The process according to claim 1,wherein the monomer is methyl methacrylate.